2-diloweralkylamino-alkoxy-3-methyl-benzoic acid esters



United States Patent f Claims priority, application Germany February 21,1957 7 Claims. (Cl. 260-471) This invention'relates to and has as itsobject the production of novel amino alkyl aryl ethers which have beenfound to constitute excellent anesthetics of long lasting action.

The novel amino alkyl aryl ethers, in accordance with the invention,have the general formula:

COOR

RI! OR-N RIII H8. 7' I in which R is a methyl or ethyl radical, Rfalower divalent alkyl radical, haVing for example, up to 3 carbon atoms,R" a lower alkyl radical and preferably an ethyl or methyl radical, andR a lower alkyl radical-or hydrogen, and preferably an ethyl or methylradical. R" and R are preferably the same radical, and more preferablyboth methyl or ethyl radicals.

R and R may, together with the nitrogen, form a heterocyclic ring suchas a pyrrolidine, piperidine, morpholine or piperazine ring. When R" andR form a ring with the nitrogen atom, the radical represented by ppreferably represent the piperidino ormorpholino radical.

The novel compounds, in accordance with the invention, may be preparedby reacting an alkyl o-cresotate with a reactive ester of acorresponding tertiary amino alcohol, preferably in the presence of anacid acceptor such as an alkali hydroxide, alkali carbonate, alkalimetal alcoholate, or the like, and in the additional presence of asolvent. Particularly suitable reactive esters of the amino alcohols arethe hydrohalic esters and the alkylor arylsulfonic esters. Examples ofsuitable amino alcohols which form the alcohol components of the started7 2,914,552 Patented ov. 24, 11959 monoalkylamino or dialkylamino group,astor example, a hydroxyl group, a halogen atom, or a nitrile orcarboxamide group, and this substituent is subsequently converted intothe dialkyl or amino group. Thus forexample, the alkyl o-cresotate. isfirst of all reacted with a haloalcohol, a dihaloalcohol, or an alkylorarylsulfonic ester of a haloal cchol, and the hydroxyl group or thehalogen atom is then exchanged by the monoor dialkylamino group in theconventional manner. Alternatively, a phthalimidoalkyl halide, ahalocarboxamide, or a nitrile of a halqcarboxylic acid, for example, maybe 7 reacted with an alkyl o-cresotate, the phthalimido, carboxamide orriitrile group in the reaction product formed converted intoan aminogroup, in the conventional mannet, and the latter alkylated according tofamiliar methods. If it is desired to prepare aminopropyl ethers of thealkyl o-cresotate, the latter may also be reacted with the correspondingacrylic acid derivatives in the presence of suitable catalysts, to formanalogous intermediate esters include ,B-dimethyland[i-diethylaminoethanolf ,6- and 'y-dimethylaminopropanol, -N-piperidinoand p-N-pyrrolidinoethanol, N -morpholinoethanol or 'N-(NT- -panols. Ifthe end products are to contain a secondary amino group, amino alcoholsshould be used which contain a tertiary amino group which may besubsequently converted into a secondary one. For this purpose N-benzyl-N-alkyl-amino alcohols are preferred. The benzyl group may beremoved and substituted by a hydrogen atom using conventional methodsafter the N-benzyl- N-alkyl-amino ethers of the o-cresotate has beenformed. The removal and hydrogen substitution may be effected, forexample, by catalytic hydrogenation in the presence of a noble metalcatalyst.

The monoalkylamino or dialkylamino alkyl radical can also be synthesizedstep by step. For this purpose, an alkyl o-cresotate is reacted withreactive esters of alcohols bearing a substituent which is convertibleinto a products. Finally, it is possible to start with dialkylaminoalkylcarbonates of the alkyl o-cresotate and then to split off carbon dioxide from these esters by heating, possibly in'the presence of catalysts.

The novel aminoalkyl aryl ethers, in accordance with the invention, arecolorless or yellowish substances which are distillable in .vacuo andform readily soluble salts f with mineral acids or organicjacids, Thenovel ethers as such or in the form of their salts constitute highlyeifective local anesthetics which are distinguished by their longlasting action, making the same excellently suited for use in veterinarymedicine and as surface anesthetics for the dental practice. For thispurpose, thecompounds may be administered as such, or in the form oftheir salts,

such as their water soluble salts, with mineral or organic acids, andparticularly in the form of their hydrochloric acid salts by injection,in the conventional manner. The compounds when used as local anestheticsshow very'low toxicity and a very rapid onsetof action.

As contrasted to the Z-methyl-6-carbalkoxy-N-alkylaminoacylanilides ofour copending application Serial No. 610,728, filed September 19, 1956;the novel ethers,

in accordance with the invention, show a much longer duratlon of action,and, in some cases, even a more rapid onset of action, so that the sameare more highly suited for veterinary practice. I

As are contrasted to the known corresponding amino alkyl aryl etherswhich do not contain the methyl group, in the ortho position Withrespect to the ether oxygen on the aromatic nucleus, the compounds, inaccordance with the invention, have a much longer duration of action,and, at least as rapid an onset of action.

tion and not limitation: a

The following examples are given by way of illustra-i Example 1 V v 41.5g. of methyl o-cresotate is added to a solution of 5.8 g. of sodium in200 ml. of methanol, and the methanol is then distilled 013? to thegreatest extent possible,"

using vacuum in the end. After drying, the finely pulverized flaskresidue is suspended in 200 ml. of dry toluene. 30 g. ofdimethylaminoethyl chloride diluted with an equal volume of toluene isslowly passed into the boiling mixture, followed by boiling under areflux condenser for 24 hours. When cool, the toluene solution is washedfirst with water, causing the precipitate .to dissolve, and

cipitated from the HCl solution carbonate solution, and after removal ofthe solvent the residue is distilled in vacuo, yielding 30 g. of themethyl caustic sodasolution to removeany unreacted starting material,and finally again with,water..- Now the toluene solutionis extractedwith an approximately twice-normal hydrochloric acid, the base is, prebymeans of potassium 3 of Z-(fl-dimethyl-aminoethoxy)-3-methylbenzoic Theester acid, which is a colorless oil of B.P. 134-136.

readily water-soluble hydrochloride melts at 127.

The following compounds can be prepared in analogous z'oate, and methylZ-(fi-dimethylamino-ethoxy)-benzoate were tested on albino rats. Thecompounds were in- ;ected around the caudal root, in accordance with thefashion: 5 Luckener method as modified by Wirth (Arch. exp. Path. Methyl2-( -dimethylammopropoxy)-3-methylbenzoate, Pharm. 216, p. 81, 1952),and the sensitivity to pain B.P. 149-152, hydrochloride M.P. 90-91. wasdetermined with the aid of a defined electric stimuli. MethylZ-(fi-diethylaminoethoxy) 3 methylbenzoate, The results of the testindicating the number of animals B.P. 147-149, hydrochloride M.P. 122.treated, the percent of concentration of the compounds, Example 2 1 theonset of the anesthetic action in minutes and the duration of theanesthetic action in minutes is shown in 41.5 g. of methyl o-cresotateis added to a sodium the following tabl no. of 00110., onset of durationFormula: animals percent aetlonln of action mm. mmm.

COOCH;

11,0ooc--o-cm-cn-crn-N(om), m 0.5 3 43 COOCH:

(C =):N( |)z 10 0. 5 1 as methylate solution prepared from 5.8 g. ofsodium and 200 ml. of methanol. Into this mixture 40 g. of N-morpholinoethyl chloride is instilled at boiling temperature under areflux condenser. After another 8 hours of boiling the product isallowed to cool, insoluble components are filtered off by suction, andthe filtrate is evaporated under vacuum. The residue is taken up withbenzene and worked up further as described in Example 1. Obtained is25.1 g. of methyl Z-(fl-N-morpholinoethoxy)-3-methylbenzoate, whichforms a colorless oil boiling under 5 mm. pressure at 190192. Thehydrochloride melts at 180-181.

Example 3 36 g. of ethyl o-cresotate is added to a sodium ethylatesolution prepared from 4.6 g. of sodium and 150 ml. of alcohol. Afterfurther addition of 2 g. of sodium iodide g. of B-dimethylaminopropylchloride: is instilled into the boiling mixture, and boiling iscontinued for 8 hours. After cooling, the product is suction-filtered,the solvent is expelled under vacuum, and the residue is dissolved inbenzene. The benzene solution so obtained is processed further asdescribed in Example 1. Vacuum distillation then yields 26.5 g. of ethylZ-(fi-dimethylaminopropoxy)-3-methylbenzoate of B.P.., 145-149,representing a yellowish oil. The hydrochloride melts at 143- 144".

The analogous procedure may be followed to prepare these compounds:

Ethyl 2-(fl-N-piperidinoethoxy) 3 methylbenzoate, B.P. 196-198";hydrochloride M.P. 111-112".

Ethyl Z-(y-diethylaminopropoxy) 3 methylbenzoate, B.P. 161-162".

Ethyl 2-(fi-N-morpholinoethoxy) 3 methylbenzoate, B.P. 188-192";hydrochloride M.P. 140.5-141.

Ethyl 2 (B-dimethylaminoethoxy)-3-methylbenzoate, B.P. 151; phosphateM.P. 93-95.

Example 4 In order to illustrate the anesthetic efiect of compounds, inaccordance with the invention, and compare the same with the known aminoalkyl aryl ethers which do not contain the methyl radical in the orthoposition on the aromatic nucleus and the anesthetic etfect' of methyl2-(' -dimethylamino-propoxy)-3-methylbenzoate,

As may be noted, the duration of action of the compounds, in accordancewith the invention, are many times longer than that of the knowncompounds, while the onset of action may be favorably compared.

We claim:

1. A member selected from the group consisting of compounds having thegeneral formula:

in which R is a member selected from the group consisting of methyl andethyl radicals, R is a lower divalent alkyl radical, R" is a lower alkylradical, R is a member selected from the group consisting of hydrogenand lower alkyl radicals, and acid addition salts of said compound.

2. Methyl 2 (5 dimethylaminoethoxy) -3-methylbenzoate.

'3. Methyl benzoate.

4. Methyl 2 (,8 diethylaminoethoxy) 3-methylbenzoate.

5. Ethyl 2 (B dimethylaminopropoxy)-3-methylbenzoate.

6.. Ethyl 2 ('y diethylarninopropoxy) 3-methylbenzoate, B.P. 161-162".

7. Ethyl 2 (i3 dimethylaminoethoxy) 3-methylbenzoate, B.P. 151;phosphate M.P. 93-95 2 ('y diethylaminopropoxy) 3 methyl- ReferencesCited in the file of this patent UNITED STATES PATENTS 2,810,719 Mooreet a1 Nov. 22, 1957 FOREIGN PATENTS 137,144- Switzerland Dec. 15, 1929OTHER REFERENCES Moore et al.: I.A.C.S., vol. 79, pp. 5633-6 (1956).Sakera et al.: Experientia, vol. 11, pp. 275-276 55).

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THEGENERAL FORMULA: